Levobupivacaine and analogues thereof such as ropivacaine are useful as local anaesthetics. These (S)-enantiomers are of increasing interest as analgesics having a higher therapeutic index than the corresponding racemates. Known syntheses have various disadvantages.
Tullar et al, J. Med. Chem. 14(9):891-2 (1971), and GB-A-1180712, describe the use of natural (R,R)-tartaric acid as the resolving agent for the separation of levobupivacaine and its antipode. 2 Molar equivalents of the base are used per molar equivalent of the acid resolving agent. For the preparation of levobupivacaine on an industrial scale, this is impractical, as the (R)-bupivacaine (R,R)-tartrate salt crystallises first, necessitating additional processing and therefore lowering the overall operating efficiency.
Further, for separation of levobupivacaine from its antipode, the method described in the prior art does not give reproducible yields of the tartrate salt, and the diastereomeric excess is variable.
This prior art does not describe a consistently reproducible process. Experiments sometimes failed, using the known conditions.
Federsel et al, Acta. Chem. Scand. B41:757-761 (1987), disclose the use of 0.52 equivalents of the resolving agent dibenzoyl tartrate, en route to the (S)-enantiomer of formula I when R.dbd.H. Water of crystallisation only is present. The resolving agent is costly.